A feature of post-traumatic or post-cardiac surgical progressive lung injury is pulmonary hypertension secondary to increased pulmonary vascular resistance (PVR). At least early in the course of acute lung injury this increased PVR is largely due to avid pulmonary vascular smooth muscle constriction, even in the absence of hypoxia. The damage to the vascular endothelium and vascular smooth muscle in the adult respiratory distress syndrome is histologically well documented 5-11. It follows that this damage may produce abnormalities in pulmonary vasomotor control mechanisms. Such abnormalities may help explain the avid pulmonary vasoconstriction of acute lung injury. Physiologically, the principle pulmonary vasoconstrictor is hypoxia. 12,14 On the other hand, the principle intracellular mechanisms of vasodilation are mediated through cAMP or cGMP. cGMP mechanisms may be endothelial-dependent or endothelial-independent. 3 When normal vasodilating mechanisms are deranged, the unchecked vaso-constricting response to hypoxia may be exaggerated. 15,16,17 The mechanistic balance of vasoconstriction and vasodilation in pulmonary vascular smooth muscle tone has not previously been related to progressive lung injury. Therefore, this study proposes to examine altered mechanisms of pulmonary vasomotor control with progressive acute lung injury. Isolated pulmonary arterial rings will be used to study the following pulmonary arterial vasomotor control mechanisms: 1. Endothelial-dependent cGMP vasodilation (response to Acetylcholine) 2. Endothelial-independent cGMP vasodilation (response to Nitroprusside) 3. Beta adrenergic cAMP vasodilation (response to isoproterenol) 4. The vasoconstricting response to hypoxia and its relation to pulmonary arterial cGMP and cAMP content. Our laboratory has developed a model of progressive lung injury consistent with clinical post-traumatic pulmonary insufficiency. 18-20 In this model endotoxin-induced pulmonary endovascular neutrophil accumulation is related to lung myeloperoxidase (MPO) content. Lung leak induced by endotoxin and N-formyl-neoleucyl-leucyl-phenylalnine (FNLP) is related to I125 albumin accumulation. We will use this model to relate progressive lung injury as evidenced by 1) increasing pulmonary neutrophils and 2) lung leak to specific derangement in the mechanisms of pulmonary vasomotor control delineated above. Expected is a characterization of abnormal pulmonary arterial vasomotor control. Its development will be temporally correlated with the evolution of acute lung injury. An understanding of the alteration in biochemical mechanisms may then be correlated with functional changes. Such an understanding should provide a basis for practical therapies.